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Radiobiological Effectiveness and Its Role in Modeling Secondary Cancer Risk for Proton Therapy
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Volume 96 Number 2S Supplement 2016 Takada: None. M. Fujiwara: None. T. Tsujimura: None. N. Kamikonya: None. S. Hirota: None.
3374 Radiobiological Effectiveness and Its Role in Modeling Secondary Cancer Risk for Proton Therapy A.M. Madkhali,1,2 C. Timlin,3 and M. Partridge3; 1King Saud University, Riyadh, Saudi Arabia, 2CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford and King Saud University, Oxford, United Kingdom, 3University of Oxford, Oxford, United Kingdom Purpose/Objective(s): In proton therapy, a radiobiological effectiveness ratio (RBE) of 1.1 (RBE1.1) is often used. In reality, RBE depends on dose, linear energy transfer (LET), biological end point, and tissue type. Using a value of RBE that may be not accurate may affect dose calculation and hence, outcome. Materials/Methods: We used an in-house built code for modelling malignant induction probability (MIP) from voxel-by-voxel dose map (Timlin 2014) and implement a published model to calculate structure-specific RBE, recalculate dose and MIP, and compare the outcomes with initial calculations using RBE1.1. MIP was calculated using linear quadratic (LQ), linear (LIN), and linear-no-threshold (LNT) models for proton therapy plans for an adult and a teenage patient diagnosed with medulloblastoma (MB). The MIP was then re-calculated using the RBE model by Dale and Jones which is a function of dose (d), a and b and RBEmin and RBEmax: RBEZ(-a+O(a^2+4bd(〖RBE〗_max a+〖RBE〗_(min )^2 bd)))/2bd. Results: Results are shown in Table 1. The difference in MIP by using RBE1.1 and RBEMinMax is w2-3%. The effect on mean dose varies between different organs and is between 6% and 8%. Clinical implications due to difference in RBE depend on beam characteristics, dose, structures concerned, and the volume irradiate. Abstract 3374; Table 1. Medulloblastoma - Adult Model LQ LIN LNT
Model LQ LIN LNT
Name Right lung Left lung Nasopharynx Right kidney Left kidney Left parotid Right parotid Thyroid Oral cavity
RBE1.1
RBEMinMax
RBE1.1:RBEMinMax
0.099 0.078 0.643
0.097 0.076 0.655
1.03 1.03 0.98
(a) Medulloblastoma -Teen RBE1.1 RBEMinMax 0.068 0.066 0.057 0.056 0.554 0.567 (b) Mean Dose (Gy) - Adult RBE1.1 RBEMinMax 1.41 1.50 1.36 1.45 4.16 4.48 0.54 0.58 1.10 1.16 4.44 4.75 2.15 2.30 0.19 0.20 0.04 0.04
RBE1.1:RBEMinMax 1.02 1.02 0.98
RBE1.1:RBEMinMax 0.94 0.94 0.93 0.94 0.94 0.94 0.93 0.92 0.92
Table 1: Values of whole body MIP using RBE of 1.1 (RBE1.1) and RBE using the described model (RBEMinMax) and the relationship between them for the adult (a) and the teenage patient (b). (c) Mean dose for selected structures from the adult patient’s plan using RBE1.1 and RBEMinMax and the relation between them.
Conclusion: Using RBE1.1 makes proton therapy dose and dose-dependent predictions less accurate. Our results using a RBE calculation model show that decreased accuracy may have clinical implications, which agrees with published literature (Jones 2012; Jones, 2014), and may affect secondary cancer risk and normal tissue complication probability calculations as well. Author Disclosure: A.M. Madkhali: None. C. Timlin: None. M. Partridge: None.
3375 The Combination of Ionizing Radiation and Toll-Like Receptor 7/8 Agonists Creates Local and Abscopal Tumor Immune Responses In Vivo N.H. Nicolay,1,2 S. Scho¨lch,1 C. Rauber,1 R. Lopez Perez,1 J. Debus,1,2 and P.E. Huber1,2; 1German Cancer Research Center, Heidelberg, Germany, 2Heidelberg University Hospital, Heidelberg, Germany Purpose/Objective(s): Radiation therapy is a mainstay of local tumor treatment, including cancers of the gastrointestinal tract. Ionizing radiation has been shown to induce local and abscopal immunological effects. However, immune effects have only been inconsistently observed after radiotherapy alone. Therefore, combining radiotherapy with immune therapies may help to augment these effects. Here, we investigated a combination of ionizing radiation with the toll-like receptor (TLR) 7/8 agonist 3M-011 both in vitro and in mouse models of colorectal and pancreatic cancers. Materials/Methods: Subcutaneous and orthotopic colorectal and pancreatic tumors were established in BALB/c and C57Bl/6 mice. Mice were treated with the TLR 7/8 agonist 3M-011 and 5 radiotherapy fractions of 2 Gy. Kinetics of tumor growth and metastatic spread were visualized by positron emission tomography, and blood and tumor samples were assessed for cytokine levels. Selective depletion of individual immune cells and cytotoxicity assays were applied to identify the immune cell populations involved in the therapy-induced immune reaction and to elucidate the underlying mechanistic effects. The specificity of the immune reaction was demonstrated by ELISPOT assays. Results: We observed that combining ionizing radiation with the TLR 7/8 agonist strongly inhibited tumor growth in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer and resulted in complete remission in about 50% of animals. Importantly, addition of the TLR agonist markedly enhanced the effects of ionizing radiation regarding both its local and distant anti-tumor activity. Depletion experiments demonstrated that the cytotoxic effects of the combination treatment were mediated by NK and CD8 T cells through monocyte-derived IL-6 stimulation; NK and CD8 cell activation required priming by CD11c+ dendritic cells. ELISPOT assays confirmed the specificity of the observed immune reaction. Cytokine profiling revealed that combining the TLR7/8 agonist with ionizing radiation increased levels of MCP-1, IL-6, IFN-gamma, and TNF-alpha, thereby shifting the cytokine equilibrium toward a proinflammatory state. Conclusion: Our data demonstrate that a combination of radiation therapy and TLR7/8 agonists could induce strong and significant local and systemic anti-tumor immune responses; these findings suggest that TLR7/8 agonists are potent adjuvant agents in combination with photon radiotherapy for the treatment of gastrointestinal cancers. This combination of radiotherapy and immune therapy may be further investigated regarding its translation into clinical studies. Author Disclosure: N.H. Nicolay: None. S. Scho¨lch: None. C. Rauber: None. R. Lopez Perez: None. J. Debus: None. P.E. Huber: None.
3376 Biological Effects of a Radiation Hormesis Sheet Emitting Very Low-Dose-Rate g Rays C. Sugie,1 Y. Shibamoto,2 S. Hashimoto,3 T. Tsuchiya,1 M. Matsuo,4 T. Kawai,1 and H. Iwata5; 1Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, 2Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, 3Nagoya Proton Therapy Center, Nagoya, Japan, 4Gifu University, Gifu, Japan, 5 Department of Radiation Oncology, Nagoya Proton Therapy Center, Nagoya City West Medical Center, Nagoya, Japan Purpose/Objective(s): Radiation hormesis hypothesis indicates various beneficial effects of low-dose radiation on living organisms. The radioadaptive response as defined by the induction of radioresistance to subsequent higher doses of ionizing radiation by pretreatment with low radiation doses is regarded as one of the beneficial effects of low-dose
Volume 96 Number 2S Supplement 2016 Takada: None. M. Fujiwara: None. T. Tsujimura: None. N. Kamikonya: None. S. Hirota: None.
3374 Radiobiological Effectiveness and Its Role in Modeling Secondary Cancer Risk for Proton Therapy A.M. Madkhali,1,2 C. Timlin,3 and M. Partridge3; 1King Saud University, Riyadh, Saudi Arabia, 2CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford and King Saud University, Oxford, United Kingdom, 3University of Oxford, Oxford, United Kingdom Purpose/Objective(s): In proton therapy, a radiobiological effectiveness ratio (RBE) of 1.1 (RBE1.1) is often used. In reality, RBE depends on dose, linear energy transfer (LET), biological end point, and tissue type. Using a value of RBE that may be not accurate may affect dose calculation and hence, outcome. Materials/Methods: We used an in-house built code for modelling malignant induction probability (MIP) from voxel-by-voxel dose map (Timlin 2014) and implement a published model to calculate structure-specific RBE, recalculate dose and MIP, and compare the outcomes with initial calculations using RBE1.1. MIP was calculated using linear quadratic (LQ), linear (LIN), and linear-no-threshold (LNT) models for proton therapy plans for an adult and a teenage patient diagnosed with medulloblastoma (MB). The MIP was then re-calculated using the RBE model by Dale and Jones which is a function of dose (d), a and b and RBEmin and RBEmax: RBEZ(-a+O(a^2+4bd(〖RBE〗_max a+〖RBE〗_(min )^2 bd)))/2bd. Results: Results are shown in Table 1. The difference in MIP by using RBE1.1 and RBEMinMax is w2-3%. The effect on mean dose varies between different organs and is between 6% and 8%. Clinical implications due to difference in RBE depend on beam characteristics, dose, structures concerned, and the volume irradiate. Abstract 3374; Table 1. Medulloblastoma - Adult Model LQ LIN LNT
Model LQ LIN LNT
Name Right lung Left lung Nasopharynx Right kidney Left kidney Left parotid Right parotid Thyroid Oral cavity
RBE1.1
RBEMinMax
RBE1.1:RBEMinMax
0.099 0.078 0.643
0.097 0.076 0.655
1.03 1.03 0.98
(a) Medulloblastoma -Teen RBE1.1 RBEMinMax 0.068 0.066 0.057 0.056 0.554 0.567 (b) Mean Dose (Gy) - Adult RBE1.1 RBEMinMax 1.41 1.50 1.36 1.45 4.16 4.48 0.54 0.58 1.10 1.16 4.44 4.75 2.15 2.30 0.19 0.20 0.04 0.04
RBE1.1:RBEMinMax 1.02 1.02 0.98
RBE1.1:RBEMinMax 0.94 0.94 0.93 0.94 0.94 0.94 0.93 0.92 0.92
Table 1: Values of whole body MIP using RBE of 1.1 (RBE1.1) and RBE using the described model (RBEMinMax) and the relationship between them for the adult (a) and the teenage patient (b). (c) Mean dose for selected structures from the adult patient’s plan using RBE1.1 and RBEMinMax and the relation between them.
Conclusion: Using RBE1.1 makes proton therapy dose and dose-dependent predictions less accurate. Our results using a RBE calculation model show that decreased accuracy may have clinical implications, which agrees with published literature (Jones 2012; Jones, 2014), and may affect secondary cancer risk and normal tissue complication probability calculations as well. Author Disclosure: A.M. Madkhali: None. C. Timlin: None. M. Partridge: None.
3375 The Combination of Ionizing Radiation and Toll-Like Receptor 7/8 Agonists Creates Local and Abscopal Tumor Immune Responses In Vivo N.H. Nicolay,1,2 S. Scho¨lch,1 C. Rauber,1 R. Lopez Perez,1 J. Debus,1,2 and P.E. Huber1,2; 1German Cancer Research Center, Heidelberg, Germany, 2Heidelberg University Hospital, Heidelberg, Germany Purpose/Objective(s): Radiation therapy is a mainstay of local tumor treatment, including cancers of the gastrointestinal tract. Ionizing radiation has been shown to induce local and abscopal immunological effects. However, immune effects have only been inconsistently observed after radiotherapy alone. Therefore, combining radiotherapy with immune therapies may help to augment these effects. Here, we investigated a combination of ionizing radiation with the toll-like receptor (TLR) 7/8 agonist 3M-011 both in vitro and in mouse models of colorectal and pancreatic cancers. Materials/Methods: Subcutaneous and orthotopic colorectal and pancreatic tumors were established in BALB/c and C57Bl/6 mice. Mice were treated with the TLR 7/8 agonist 3M-011 and 5 radiotherapy fractions of 2 Gy. Kinetics of tumor growth and metastatic spread were visualized by positron emission tomography, and blood and tumor samples were assessed for cytokine levels. Selective depletion of individual immune cells and cytotoxicity assays were applied to identify the immune cell populations involved in the therapy-induced immune reaction and to elucidate the underlying mechanistic effects. The specificity of the immune reaction was demonstrated by ELISPOT assays. Results: We observed that combining ionizing radiation with the TLR 7/8 agonist strongly inhibited tumor growth in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer and resulted in complete remission in about 50% of animals. Importantly, addition of the TLR agonist markedly enhanced the effects of ionizing radiation regarding both its local and distant anti-tumor activity. Depletion experiments demonstrated that the cytotoxic effects of the combination treatment were mediated by NK and CD8 T cells through monocyte-derived IL-6 stimulation; NK and CD8 cell activation required priming by CD11c+ dendritic cells. ELISPOT assays confirmed the specificity of the observed immune reaction. Cytokine profiling revealed that combining the TLR7/8 agonist with ionizing radiation increased levels of MCP-1, IL-6, IFN-gamma, and TNF-alpha, thereby shifting the cytokine equilibrium toward a proinflammatory state. Conclusion: Our data demonstrate that a combination of radiation therapy and TLR7/8 agonists could induce strong and significant local and systemic anti-tumor immune responses; these findings suggest that TLR7/8 agonists are potent adjuvant agents in combination with photon radiotherapy for the treatment of gastrointestinal cancers. This combination of radiotherapy and immune therapy may be further investigated regarding its translation into clinical studies. Author Disclosure: N.H. Nicolay: None. S. Scho¨lch: None. C. Rauber: None. R. Lopez Perez: None. J. Debus: None. P.E. Huber: None.
3376 Biological Effects of a Radiation Hormesis Sheet Emitting Very Low-Dose-Rate g Rays C. Sugie,1 Y. Shibamoto,2 S. Hashimoto,3 T. Tsuchiya,1 M. Matsuo,4 T. Kawai,1 and H. Iwata5; 1Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, 2Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, 3Nagoya Proton Therapy Center, Nagoya, Japan, 4Gifu University, Gifu, Japan, 5 Department of Radiation Oncology, Nagoya Proton Therapy Center, Nagoya City West Medical Center, Nagoya, Japan Purpose/Objective(s): Radiation hormesis hypothesis indicates various beneficial effects of low-dose radiation on living organisms. The radioadaptive response as defined by the induction of radioresistance to subsequent higher doses of ionizing radiation by pretreatment with low radiation doses is regarded as one of the beneficial effects of low-dose